Oral contraceptive

ABSTRACT

This invention provides a bridged triphasic combination progestin/estrogen oral contraceptive regimen comprising the administration of a contraceptive progestin/estrogen combination for 23-25 days consecutive days beginning on the first day of menses, followed by the administration of an estrogen for 3-5 days following the administration of the estrogen/progestin combination, so that the total period of administration is 28 days per 28 day cycle. Particularly preferred progestins of this invention are trimegestone, dienogest, and drospirenone.

BACKGROUND OF THE INVENTION

This application claims the benefit of U.S. Provisional Application No.60/022,624, filed Jul. 26, 1996.

The vast majority of oral contraceptives consist of a combination of aprogestin and estrogen that are administered concurrently for 21 daysfollowed either by a 7 day pill free interval or by the administrationof a placebo for 7 days in each 28 day cycle. The most important aspectsof a successful oral contraceptive product are effective contraception,good cycle control (absence of spotting and breakthrough bleeding andoccurrence of withdrawal bleeding), and minimal side effects.Combination oral contraceptives have traditionally acted by suppressionof gonadotropins. In addition, it appears that the progestin componentis primarily responsible for contraceptive efficacy through inhibitionof ovulation, and other peripheral effects which include changes in thecervical mucus (which increase the difficulty of sperm entry into theuterus) and the endometrium (which reduce the likelihood ofimplantation). The estrogenic component intensifies the anovulatoryeffect of the progestin, and is also important for maintaining cyclecontrol.

Since the introduction of oral contraceptives (OCs) over aquarter-century ago, research has been directed toward developingpreparations that minimize the potential for side effects whilemaintaining efficacy and normal menstrual patterns. The first-generationOCs contained more progestin and estrogen than was necessary to preventconception. Adverse hemostatic and metabolic changes, clinical problems,and side effects were associated with these high-dose preparations. In1978, the World Health Organization (WHO) recommended that the focus ofOC research should be the development of products containing the lowestpossible dose levels of estrogen and progestin.

The first reductions in steroid content in a combination pill werefocused on estrogen because it, rather than progestin, was thought to berelated to the most serious side effects. Reduction in progestin contentfollowed, as evidence mounted that lowering progestin intake might lowerthe risk of cardiovascular complications such as stroke and ischemicheart disease. Kay CR, Am J Obstet Gynecol 142:762 (1982)!. However,this evidence was not as clear as that implicating estrogen inthromboembolic disorders. Inman WHW, Br Med J 2:203 (1970); Stolley PD,Am J Epidemiol 102:197 (1975)!. The need for a balance between estrogensand progestins to minimize adverse effects on carbohydrate metabolismand on lipid and lipoprotein levels was also recognized. Bradley DD, NEngl J Med 299:17 (1978); Wynn V, Lancet 1:1045 (1979)!. Researchersthen found that the synergistic action between progestin and estrogen ina balanced ratio successfully inhibited ovulation at low levels of bothcomponents.

Research into low-dose progestins was advanced significantly by thedevelopment of norgestrel (Ng) and levonorgestrel (LNg). Levonorgestrelis the biologically active moiety of racemic norgestrel. It is stronglyprogestational, has no inherent estrogenic activity, is antiestrogenic,and possesses good biologic activity. The contraceptive effects oflevonorgestrel are manifested throughout thehypothalamic-pituitary-gonadal-target organ axis.

Ethinyl estradiol (EE) is the estrogen most frequently used incombination OCs. In attempts to fulfill the WHO objective, the dosage ofEE in marketed OC formulations has been steadily reduced from that foundin earlier OCs. Thromboembolic mortality decreased when the amount ofsynthetic estrogen in OC formulations was reduced from 100 μg to 50 μg.Subsequently, a significant reduction in fatal myocardial infarctionswas reported for women using OCs with 30 μg of EE rather than 50 μg ofEE. Meade TW, Br Med J 280:1157 (1980)!.

In keeping with the goal of reducing the total steroidal dosage, whilemaintaining contraceptive efficacy, good cycle control, and minimizingside effects, numerous regimens have been developed in which theprogestin/estrogen combination is administered either as a fixed dosagecombination (monophasic) or as biphasic or triphasic regimens in whichthe dosage of the combination is varied either once or twice throughoutthe menstrual cycle. In these regimens, the progestin/estrogencombination is typically administered for 21 days followed by either a7-day pill free period or the administration of a non-contraceptiveplacebo (or iron supplement) for 7 days. In these regimens,3-ketodesogestrel (3-KDSG), desogestrel (DSG), levonorgestrel (LNg),gestodene (GTD), norgestrel (NG), and norethindrone (NE) are typicallyused as the progestin while ethinyl estradiol (EE); 17β-estradiol, andmestranol are typically the estrogenic components. Other progestins lessfrequently used include drospirenone (DRSP) and dienogest (DGST).

An oral contraceptive product containing a combination of 3 mg DGST and30 μg EE for 21-day administration per cycle is marketed in Germany.

Several examples of attempts at reducing the total steroidal dosage areprovided below.

Lachnit (PCT Publication WO 95/26730) discloses bridged regimensconsisting of the administration of a combination of aprogestin/estrogen combination (50-125 μg LNg and 10-40 μg EE) for thefirst 23-24 days of the menstrual cycle followed by the administrationof an estrogen (2-40 μg EE) for 4-10 days for a total administration ofat least 28 days per cycle. The use of 100-300 μg drospirenone and 10-40μg EE as the 23-24 day progestin/estrogen combination is disclosed.Lachnit also discloses a triphasic plus bridging regimen (4-9 days, 4-9days, 9-13 days, and 28 days for the three phases and estrogen phase,respectively) in which a combination of 50 μg LNg and 20 μg EE areadministered in the first phase, a combination of 75 μg LNg and 25 μg EEare administered in the second phase, a combination of 100 μg LNg and 20μg EE are administered in the third phase, and 10 μg EE is administeredin the estrogen phase. Other progestins disclosed include GTD, DSG,3-KDSG, DRSP, cyproterone acetate, norgestimate, and norethisterone.

Erlich (German Patent DE 4,104,385 Cl and U.S. Pat. No. 5,280,023)discloses sequential contraceptive regimens consisting of theadministration of an estrogen which effects a disturbance of folliclestimulation, followed by the administration of a combination of aprogestin/estrogen in a dose at least adequate to inhibit ovulation. Theregimen is administered for a total of 28 days per cycle. It ispreferred that the estrogen is administered for 5-14 days per cycle andthe progestin/estrogen combination is administered for 23-14 days percycle, so that the total administration is for 28 days per cycle.Specific regimens include (a) 4 mg estradiol for 7 days followed by 21days of the combination of 1 mg norethisterone acetate and 4 mgestradiol; (b) 2 mg estradiol valerate for 7 days followed by 21 days ofthe combination of 2 mg chlormadinone acetate and 4 mg estradiolvalerate; and (c) 20 μg EE followed by 18 days of the combination of 150μg LNg and 20 μg EE. Regimen (c) in Erlich provides a total steroidalload of 2.7 mg of LNg and 560 μg EE per 28 day cycle.

Moore (DE 4313926 Al) discloses bridged triphasic regimens consisting ofthe administration of a combination of 10-50 μg LNg and 5-20 μg EE fromdays 1-7 of the menstrual cycle; of 50-75 μg LNg and 5-20 μg EE fromdays 8-14 of the menstrual cycle; of 75-125 μg LNg and 5-20 μg EE fromdays 15-21 of the menstrual cycle; and 5-20 μg EE from days 22-28 of themenstrual cycle.

Oettel (EP 696,454 A2) discloses a three phase contraceptive regimen inwhich the first phase consists of the administration for 3-4 days of acomposition containing at least one biogenic estrogen; the second phaseconsists of the administration for 20-22 days of at least one biogenicestrogen and at least one progestin (progesterone, DGST, desogestrel,3-KDSG, GTD, LNg, norgestimate, notethisterone, norethisterone acetate,dehydrogestrone, chloimadinone acetate, cyproterone acetate,medroxyprogesterone acetate, or megestrol acetate); and the third phaseconsists of the administration for 3-4 days of a composition containingat least biogenic one estrogen.

Spona (PCT Publication WO 95/17194) discloses contraceptive regimenswhich consist of the administration of a combination of a progestin(50-75 μg GTD, 75-125 μg LNg, 60-150 μg DSG, 60-150 FIG. 3-KDSG, 100-300μg DRSP, 100-200 μg cyproterone acetate, 200-300 μg norgestimate,or >350-750 μg norethisterone) and an estrogen (15-20 μg EE or 2-6 μg17β-estradiol) for 23-24 days per cycle.

Oettel (EP 628,312 Al) discloses combination contraceptive combinationscontaining the combination of three components: a biogenic estrogen(estradiol, estrone, or estiol), a synthetic estrogen (EE or mestranol),and a progestin (LNg, desogestrel, progesterone, norethisterone acetate,DGST, chlormadinone acetate, gestodene, or cyproterone acetate). In oneembodiment, the combination is administered for 21 days followed by theadministration of placebo (or pill free) or an estrogen on days 22-28 ofthe cycle.

Upton (EP Patent Specification 253,607 B 1) teaches the use of low doseprogestin/estrogen combinations for combined hormone replacement therapyand contraception in climacteric women. Climacteric women are defined inUpton as premenopausal women around 40 years of age whose hormone levelsare waning. The climacteric woman still ovulates (albeit may haveirregular ovulation), but she still experiences many of the symptoms ofthe hypoestrogenic menopausal woman, such as insomnia, hot flushes, andirritability. Upton teaches the administration of a 23-26 day monophasicregimen of progestin/estrogen followed by a pill free or placebointerval of 2-5 days; with 24 days of progestin/estrogen administrationfollowed by a 4-day pill free or placebo administration being preferred.Upton teaches the use of a progestin selected from 25-100 μg LNg, 10-70μg GTD, 25-100 μg DSG, 25-100 μg 3-KDSG, and 85-350 μg NE used incombination with an estrogen selected from 500-2000 μg 17β-estradiol,8-30 μg EE, and 15-60 μg mestranol. Based on relative potencies, Uptonteaches that a dose of 75 μg LNg is equivalent to 35 μg of GTD, 75 μg of3-KDSG or DSG, and 250 μg NE and that a dose of 1000 μg of 17β-estradiolis equivalent to a dose of 15 μg EE and 30 μg mestranol. Upton alsoteaches that NG may be substituted for LNg, but at twice the dose.

Saitoretto (Clinica e Terapeutca 3: 399 (1974)) discloses a monophasiccontraceptive regimen consisting of the administration of a combination100 μg LNg and 20 μg EE for 21 days.

Lachnit-Fixson (U.S. Pat. No. 3,969,502) discloses biphasicprogestin/estrogen combination regimens in which a combination of 50-125μg LNg and 25-35 μg EE are administered for 10-12 days in the firstphase and 100-350 μg LNg and 30-50 μg EE are administered for 10-12 daysin the second phase. Placebo is administered for 5-7 days following theadministration of the contraceptive steroid regimen.

Lachnit-Fixson (U.S. Pat. No. 3,957,982) discloses triphasic 21-dayprogestin/estrogen regimens in which a combination of 40-90 μg LNg and20-50 μg EE is administered for 4-6 days in the first phase, 50-125 μgLNg and 30-50 μg EE is administered for 4-6 days in the second phase,and 100-250 μg LNg and 25-50 μg EE is administered for 9-11 days in thethird phase. It is preferred that the first, second, and third phasesare 6, 5, and 10 days, respectively.

Bennick (U.S. Pat. No. 5,418,228) discloses triphasic regimens whichconsist of the administration of a combination progestin/estrogen in a6-8 day phase, a second 6-8 day phase, and a third 6-8 day phase, withit being preferred that the three contraceptive steroid phases be 7 dayseach. Bennick discloses that the first contraceptive steroid phaseconsists of a progestin at a daily dosage equivalent to 75-150 μg DSGand an estrogen at a daily dosage equivalent to 20-25 μg EE; the secondcontraceptive steroid phase consists of a progestin at a daily dosageequivalent to 75-125 μg DSG and an estrogen at a daily dosage equivalentto 20 μg EE; and the third contraceptive steroid phase consists of aprogestin at a daily dosage equivalent to 75-100 μg DSG and an estrogenat a daily dosage equivalent to 20 μg EE. Placebo is administered for 7days following the 21-day contraceptive steroid period. Bennickdiscloses that the progestin may be 3-KDSG, DSG, LNg, or GTD.

Bergink (U.S. Pat. No. 5,262,408) discloses a 24 day triphasiccombination regimen in which the first 7-9 day phase consists of theadministration of a progestin at a daily dosage equivalent to 100 μg DSGand an estrogen at a daily dosage equivalent to 25 μg EE, the second 7-9day phase consists of the administration of a progestin at a dailydosage equivalent to 125 μg DSG and an estrogen at a daily dosageequivalent to 20 μg EE, and the third 7-9 day phase consists of theadministration of a progestin at a daily dosage equivalent to 50 μg DSGand an estrogen at a daily dosage equivalent to 20 μg EE. It ispreferred that the three phases be 8 days each. Following the 24 daycontraceptive steroid administration, a placebo may be administered for4 days, the 4 day interval may be pill free, or a progestin at a dosageequivalent to 25-35 μg DSG may be administered.

Boissonneault (U.S. Pat. No. 4,962,098) discloses triphasicprogestin/estrogen combinations in which the amount of the estrogeniccomponent is increased stepwise over the three phases. Contraceptivesteroid combinations are taken for 4-7 days during the first phase (5days being preferred); for 5-8 days during the second phase (7 dayspreferred); and for 7-12 days during the third phase (9 days beingpreferred). Following the administration of 21-days of the contraceptivesteroid combination, placebo is taken for 7 days. For all three phases,0.5-1.5 mg of norethindrone acetate is used in tie progestin, with 1 mgbeing preferred. 10-30 μg EE is used in the first phase, 20-40 μg in thesecond, and 30-50 μg in the third phase.

Pasquale (U.S. Pat. No. 4,921,843) discloses combinationprogestin/estrogen contraceptive regimens which contain 0.5 to 1 mg ofprogestin and an estrogen having a dose equivalent to 10-40 μg of EE.NE, LNg, D-17β-acetoxy-13β-ethyl-17α-ethinyl-gon-4-en-3-one oxime, and19-nor-17-hydroxy progesterone ester are disclosed as progestins, withNE being preferred. Specifically disclosed regimens include a uniphasicregimen (2 days of placebo, 5 days of 20 μg EE, and 21 days of acombination of 500 μg NE and 35 μg EE); a uniphasic regimen (2 days ofplacebo, 5 days of 40 μg EE, and 21 days of a combination of 500 μg NEand 35 μg EE); and a triphasic regimen (2 days of placebo; 5 days of20-40 μg EE; 7 days of a combination of 500 μg NE and 35 μg EE; 7 daysof a combination of 750 μg NE and 35 μg EE; and 7 days of a combinationof 1 mg NE and 35 μg EE).

Pasquale (U.S. Pat. No. 4,628,051) discloses triphasicprogestin/estrogen combination regimens in which contraceptive steroidis administered for 21 days. Contraceptive steroid combinations aretaken for 5-8 days during the first phase (7 days being preferred); for7-11 days during the second phase (7 days preferred); and for 3-7 daysduring the third phase (7 days being preferred). In all three phases, anestrogen at a daily dosage equivalent to 20-50 μg EE is administered incombination with a progestin having a daily dosage equivalent to 65-750μg NE in the first phase, 0.25-1.0 mg NE in the second phase, and0.35-2.0 mg NE in the third phase. A specific triphasic regimendiscloses the administration of 35 μg EE in each of the three 7-dayphases in combination with 0.5 mg, 0.75 mg, and 1.0 mg in the first,second, and third phases, respectively. A second specific triphasicregimen discloses the administration of 35 μg EE in each of the three7-day phases in combination with 50 μg, 75 μg, and 100 μg in the first,second, and third phases, respectively. A third specific triphasicregimen discloses the administration of 35 μg EE in each of the three7-day phases in combination with 25 μg, 35 μg, and 50 μg in the first,second, and third phases, respectively.

Lachnit-Fixson (U.S. Pat. No. 4,621,079) discloses triphasic 21-dayprogestin/estrogen combination regimens in which a combination of 40-70μg GTD and 20-35 μg EE is administered for 4-6 days in the first phase;50-100 μg GTD and 30-50 μg EE is administered for 4-6 days in the secondphase; and 80-120 μg GTD and 20-50 μg EE is administered for 9-11 daysin the third phase. Placebo is administered for 7 days following the21-day contraceptive steroid regimen.

Pasquale (U.S. Pat. No. 4,530,839) discloses triphasic 21-dayprogestin/estrogen combination regimens in which a dose of 20-50 μg EEis administered in all three phases in combination with acontraceptively effective daily dose of progestin in the first phase,1.5-2 times that dose of progestin in the second phase, and 2-2.5 timesthe first phase dose of progestin in the third phase. Each of the threephases is 7 days long. A specific regimen discloses 20-50 μg EE incombination with 500 μg LNg, 750 μg LNg, and 1 mg LNg during each of thethree 7-day phases, respectively.

Edgren (U.S. Pat. No. 4,390,531) discloses triphasic 21-dayprogestin/estrogen combination regimens in which a dose of 20-40 μg EE(or another estrogen in an equivalent dosage) is administered in allthree phases in combination with 0.3-0.8 mg NE (or another progestin inan equivalent dosage) for 5-8 days in the first phase, twice the dose ofNE for 7-11 days in the second phase, and the dose of NE being the sameas in the first phase for 3-7 days in the third phase. It is preferredthat each of the three phases is 7 days. Placebo is administered for 6-8days following administration of the contraceptive steroid combination.A specific regimen discloses a first phase of 7 days of 0.5 mg NE incombination with 35 μg EE, a second 7 day phase of 1.0 mg NE incombination with 35 μg EE, and a third 7 day phase of 0.5 mg NE incombination with 35 μg EE.

DESCRIPTION OF THE INVENTION

This invention provides a bridged triphasic combinationprogestin/estrogen oral contraceptive regimen for females ofchild-bearing age that provides effective contraception, good cyclecontrol, and minimal side effects while greatly reducing the totalcontraceptive steroid administered (particularly the estrogeniccomponent) per 28-day cycle. To achieve the substantial reduction in thetotal contraceptive steroid administered per cycle, the low doseprogestiniestrogen combination is administered for 23-25-days per cycleaccording to a triphasic regimen that is described below. Administrationof the contraceptive progestin/estrogen combination is begun on thefirst day of menses (day 1), and continued for 23-25 consecutive days.Following the 23-25-day administration period, an estrogen isadministered for 3-5 days to assist in maintaining good cycle control.The total administration during each cycle is 28 days.

More particularly, this invention provides a method of contraceptionwhich comprises administering to a female of child bearing age a firstphase of a combination of a progestin at a daily dosage of 40-500 μgtrimegestone, 250 μg--4 mg dienogest, or 250 μg--4 mg drospirenone, andan estrogen at a daily dosage equivalent in estrogenic activity to 10-20μg ethinyl estradiol for 3-8 days beginning on day 1 of the menstrualcycle. The same daily dosage of the progestin and estrogen isadministered for each of the 3-8 days. A second phase of a combinationof a progestin at a daily dosage of 40-500 μg trimegestone, 250 μg--4 mgdienogest, or 250 μg--4 mg drospirenone, and an estrogen at a dailydosage equivalent in estrogenic activity to 10-20 μg ethinyl estradiolis administered for 4-15 days beginning on the day immediately followingthe last day of administration of the first phase. The same daily dosageof the progestin and estrogen is administered for each of the 4-15 days.A third phase of a combination of a progestin at a daily dosage of40-500 μg trimegestone, 250 μg--4 mg dienogest, or 250 μg--4 mgdrospirenone, and an estrogen at a daily dosage equivalent in estrogenicactivity to 10-20 μg ethinyl estradiol at a daily dosage equivalent inestrogenic activity to 10-20 μg ethinyl estradiol is administered for4-15 days beginning on the day immediately following the last day ofadministration of the second phase. The same daily dosage of theprogestin and estrogen is administered for each of the 4-15 days. Thetotal administration for all three phases is 23-25 days. The dailydosage of the progestin/estrogen combination administered in any phaseis distinct from the dosage of the progestin/estrogen combinationadministered in either of the other two phases.

Following the 23-25-day period, an estrogen phase is administered inwhich an estrogen at a daily dosage equivalent to 5-20 μg ethinylestradiol is administered for 3-5 days. The total administration duringeach cycle is 28 days.

It is preferred that total administration of the progestin/estrogencombination be 24 days. Preferred phase lengths are shown in thefollowing table, with Phase Regimens A and B being most preferred forthe bridged triphasic rising regimens that are described below, andPhase Regimens E and F are most preferred for the bridged triphasicmidpeak regimens that are described below.

    ______________________________________    Phase    Phase 1 Phase 2    Phase 3                                      Estrogen Phase    Regimen  (days)  (days)     (days)                                      (days)    ______________________________________    A        7       7          10    4    B        5       5          14    4    C        5       8          11    4    D        6       6          12    4    E        7       10         7     4    F        6       12         6     4    G        6       8          10    4    H        4       8          12    4    I        5       14         5     4    J        6       10         8     4    ______________________________________

Preferred estrogens include, but are not limited to ethinyl estradiol;17β-estradiol; conjugated estrogens, USP; estrone or a salt thereof; andmestranol; with ethinyl estradiol being more preferred. Preferred saltsof estrone include, but are not limited to the sodium and piperate salt.When conjugated estrogens, USP are used as the estrogen, it is preferredthat the daily dosage is 0.3-5 mg, with a daily dose of 1.25 mgconjugated estrogens, USP being equivalent to a daily dose of 15 μgethinyl estradiol.

In one specific preferred embodiment of this invention termed a"triphasic rising regimen," the dosage of progestin is higher in thesecond phase than in the first phase and is higher in the third phasethan in the second phase. With these regimens, the third phase willgenerally have the longest duration. In general, the estrogen dosage inthe second phase is greater than the first phase, and the estrogendosage in third phase is greater than the second phase; can rise fromthe first phase to the second phase, and then remain the same for thethird phase; or can remain the same for all three phases.

The following daily dosages of a combination of trimegestone and ethinylestradiol are preferred for contraception when administered according toa triphasic rising regimen for 23-25 consecutive days beginning on thefirst day of menses, with 24 days being preferred. In these regimens, itis preferred that ethinyl estradiol is administered during the estrogenphase for 3-5 days, with 4 days being more preferred, so that the totaladministration per cycle is 28 days. The preferred phase lengths areprovided above. Of the regimens provided below, Regimen B is morepreferred. In the table below, trimegestone is abbreviated as TMG andethinyl estradiol is abbreviated as EE.

    ______________________________________    PREPERRED DAILY DOSAGES (in μg)    Phase 1       Phase 2   Phase 3   Estrogen Phase    Regimen TMG    EE     TMG  EE   TMG  EE   EE    ______________________________________    A       75     10     125  15   250  20   20    B       50     10     75   15   125  20   20    C       40     10     50   15    75  20   20    D       50     10     75   15   125  15   15    E       50     10     75   10   125  15   15    ______________________________________

The following daily dosages of a combination of dienogest and ethinylestradiol are preferred for contraception when administered according toa triphasic rising regimen for 23-25 consecutive days beginning on thefirst day of menses, with 24 days being preferred. In these regimens, itis preferred that ethinyl estradiol is administered during the estrogenphase for 3-5 days, with 4 days being more preferred, so that the totaladministration per cycle is 28 days. The preferred phase lengths areprovided above. Of the regimens provided below, Regimen B is morepreferred. In the table below, dienogest is abbreviated as DGST andethinyl estradiol is abbreviated as EE.

    ______________________________________    PREFERRED DAILY DOSAGES                                        Estrogen    Phase 1       Phase 2    Phase 3    Phase    Regimen           DGST    EE     DGST  EE   DGST  EE   EE    ______________________________________    A      750 μg                   10 μg                           1 μg                                15 μg                                     2 mg  20 μg                                                20 μg    B      500 μg                   10 μg                          750 μg                                15 μg                                     1 mg  20 μg                                                20 μg    C      750 μg                   10 μg                           1 μg                                15 μg                                     2 mg  15 μg                                                15 μg    D      500 μg                   10 μg                          750 μg                                15 μg                                     1 mg  15 μg                                                15 μg    ______________________________________

The following daily dosages of a combination of drospirenone and ethinylestradiol are preferred for contraception when administered according toa triphasic rising regimen for 23-25 consecutive days beginning on thefirst day of menses, with 24 days being preferred. In these regimens, itis preferred that ethinyl estradiol is administered during the estrogenphase for 3-5 days, with 4 days being more preferred, that the totaladministration per cycle is 28 days. The preferred phase lengths areprovided above. Of the regimens provided below, Regimen B is morepreferred. In e table below, drospirenone is abbreviated as DRSP andethinyl estradiol is breviated as EE.

    ______________________________________    PREFERRED DAILY DOSAGES                                        Estrogen    Phase 1       Phase 2    Phase 3    Phase    Regimen           DRSP    EE     DRSP  EE   DRSP  EE   EE    ______________________________________    A       2 mg   10 μg                          3 mg  15 μg                                      4 mg 20 μg                                                20 μg    B       1 mg   10 μg                          2 mg  15 μg                                      3 mg 20 μg                                                20 μg    C      500 μg                   10 μg                          1 mg  15 μg                                      2 mg 20 μg                                                20 μg    D       2 mg   10 μg                          3 mg  15 μg                                      4 mg 15 μg                                                15 μg    E       1 mg   10 μg                          2 mg  15 μg                                      3 mg 15 μg                                                15 μg    F      500 μg                   10 μg                          1 mg  15 μg                                      2 mg 15 μg                                                15 μg    ______________________________________

In another specific preferred embodiment of this invention termed a"triphasic mid-peak regimen," the dosage of progestin is typicallyhighest in the second phase. The dosage of progestin in the third phaseis generally, though not necessarily, higher than in the first phase.With these regimens, the second phase will generally have the longestduration. In general, the estrogen can rise so that the dosage in thesecond phase is greater than the first phase, and the dosage in thirdphase is greater than the second phase; can rise from the first phase tothe second phase, and then remain the same for the third phase; canremain the same for all three phases; or can be "mid-peak" so that thedose in the second phase is highest, with the dose in the third phasegenerally being higher than the first phase.

The following daily dosages of a combination of trimegestone and ethinylestradiol are preferred for contraception when administered according toa triphasic mid-peak regimen for 23-25 consecutive days beginning on thefirst day of menses, with 24 days being preferred. In these regimens, itis preferred that ethinyl estradiol is administered during the estrogenphase for 3-5 days, with 4 days being more preferred, so that the totaladministration per cycle is 28 days. The preferred phase lengths areprovided above. Of the regimens provided below, Regimen B is morepreferred. In, the table below, trimegestone is abbreviated as TMG andethinyl estradiol is abbreviated as EE.

    ______________________________________    PREFERRED DAILY DOSAGES (in μg)    Phase 1       Phase 2   Phase3    Estrogen Phase    Regimen TMG    EE     TMG  EE   TMG  EE   EE    ______________________________________    A       75     10     250  20   125  15   15    B       50     10     125  20   75   15   15    C       40     10      75  20   50   15   15    D       50     10     125  15   75   15   15    E       50     10     125  15   75   10   10    ______________________________________

The following daily dosages of a combination of dienogest and ethinylestradiol are preferred for contraception when administered according toa triphasic mid-peak regimen for 23-25 consecutive days beginning on thefirst day of menses, with 24 days being preferred. In these regimens, itis preferred that ethinyl estradiol is administered during the estrogenphase for 3-5 days, with 4 days being more preferred, so that the totaladministration per cycle is 28 days. The preferred phase lengths areprovided above. Of the regimens provided below, Regimen B is morepreferred. In the table below, dienogest is abbreviated as DGST andethinyl estradiol is abbreviated as EE.

    ______________________________________    PREFERRED DAILY DOSAGES                                        Estrogen    Phase 1       Phase 2    Phase 3    Phase    Regimen           DGST    EE     DGST  EE   DGST  EE   EE    ______________________________________    A      750 μg                   10 μg                          2 mg  20 μg                                      1 mg 15 μg                                                15 μg    B      500 μg                   10 μg                          1 mg  20 μg                                     750 μg                                           15 μg                                                15 μg    C      750 μg                   10 μg                          2 mg  15 μg                                      1 mg 15 μg                                                15 μg    D      500 μg                   10 μg                          1 mg  15 μg                                     750 μg                                           15 μg                                                15 μg    ______________________________________

The following daily dosages of a combination of drospirenone and ethinylestradiol are preferred for contraception when administered according toa triphasic mid-peak regimen for 23-25 consecutive days beginning on thefirst day of menses, with 24 days being preferred. In these regimens, itis preferred that ethinyl estradiol is administered during the estrogenphase for 3-5 days, with 4 days being more preferred, so that the totaladministration per cycle is 28 days. The preferred phase lengths areprovided above. Of the regimens provided below, Regimen B is morepreferred. In the table below, drospirenone is abbreviated as DRSP andethinyl estradiol is abbreviated as EE.

    ______________________________________    PREFERRED DAILY DOSAGES                                        Estrogen    Phase 1       Phase 2    Phase 3    Phase    Regimen           DRSP    EE     DRSP  EE   DRSP  EE   EE    ______________________________________    A       2 mg   10 μg                          4 mg  20 μg                                     3 mg  15 μg                                                15 μg    B       1 mg   10 μg                          3 mg  20 μg                                     2 mg  15 μg                                                15 μg    C      500 μg                   10 μg                          2 mg  20 μg                                     1 mg  15 μg                                                15 μg    D       2 mg   10 μg                          4 mg  15 μg                                     3 mg  15 μg                                                15 μg    E       1 mg   10 μg                          3 mg  15 μg                                     2 mg  15 μg                                                15 μg    F      500 μg                   10 μg                          2 mg  15 μg                                     1 mg  15 μg                                                15 μg    ______________________________________

It is preferred that the combination progestin/estrogen contraceptive beadministered in unit dosage form i.e., tablet or pill, with each unitproviding the entire daily dosage. It is preferred that the progestinand estrogen are admixed together in the same dosage unit. Such dosageunits can be prepared by conventional methodology that is well known toone skilled in the art. In each dosage unit, the contraceptively activeprogestin and estrogen are combined with excipients, vehicles,pharmaceutically acceptable carriers, and colorants. For example, thefollowing illustrates an acceptable composition of a contraceptiveprogestin/estrogen combination of this invention.

EXAMPLE 1

Trimegestone, 125 μg

Ethinyl estradiol, 15 μg

Microcrystaline Cellulose

Lactose, NF, Spray Dried

Polaciillin Potassium, NF

Magnesium Stearate

Opadry Pink

Polyethylene Glycol, 1500, Flakes

Water, Purified, USP

Wax E (Phalma)

For administration during the last 3-5 days of the menstrual cycle, itis preferred that the estrogen be administered in unit dosage form i.e.,tablet or pill, with each unit providing the entire daily dosage. Suchdosage units can be prepared by conventional methodology that is wellknown to one skilled in the art. In each dosage unit, the estrogen iscombined with excipients, vehicles, pharmaceutically acceptablecarriers, and colorants. For example, the following illustrates anacceptable estrogen composition of this invention.

EXAMPLE 2

Ethinyl estradiol, 15 μg

Microcrystaline Cellulose

Lactose, NF, Spray Dried

Polacrillin Potassium, NF

Magnesium Stearate

Opadry Pink

Polyethylene Glycol, 1500, Flakes

Water, Purified, USP

Wax E (Pharma)

This invention also provides a contraceptive kit adapted for daily oraladministration which comprises, 3-8 first phase dosage units eachcontaining fixed dosage of a combination of a progestin at a dailydosage of 440-500 μg trimegestone, 250 μg--4 mg dienogest, or 250 μg--4mg drospirenone, and an estrogen at a daily dosage equivalent inestrogenic activity to 10-20 μg ethinyl estradiol; 4-15 second phasedosage units each containing fixed dosage of a combination of aprogestin at a daily dosage of 40-500 ,g trimegestone, 250 μg--4 mgdienogest, or 250 μg--4 mg drospirenone, and an estrogen at a dailydosage equivalent in estrogenic activity to 10-20 μg ethinyl estradiol;4-15 third phase dosage units each containing fixed dosage of acombination of a progestin at a daily dosage of 40-500 μg trimegestone,250 μg--4 mg dienogest, or 250 μg--4 mg drospirenone, and an estrogen ata daily dosage equivalent in estrogenic activity to 10-20 μg ethinylestradiol; and 3-5 estrogen phase dosage units each containing a fixeddosage of an estrogen at a daily dosage equivalent to 5-20 μg ethinylestradiol, such that the total number of combination dosage units is 28.The daily dosage arrangements are preferably arranged in a blister packor in a dial pack type tablet dispenser. Specific referred progestinsand estrogens and the specifically preferred dosages of each combinationdosage unit are described above.

What is claimed is:
 1. A method of contraception which comprisesadministering orally to a female of child bearing age for 23-25consecutive days,a first phase combination of a progestin at a dailydosage selected from the group consisting of 40-500 μg trimegestone, 250μg--4 mg dienogest, and 250 μg--4 mg drospirenone, and an estrogen at adaily dosage equivalent in estrogenic activity to 10-20 μg ethinylestradiol for 3-8 days beginning on day 1 of the menstrual cycle,wherein the same dosage of the progestin and estrogen combination isadministered in each of the 3-8 days, a second phase combination of aprogestin at a daily dosage selected from the group consisting of 40-500μg trimegestone, 250 μg--4 mg dienogest, and 250 μg--4 mg drospirenone,and an estrogen at a daily dosage equivalent in estrogenic activity to10-20 μg ethinyl estradiol, for 4-15 days beginning on the dayimmediately following the last day of administration of the first phasecombination, wherein the same dosage of the progestin and estrogencombination is administered in each of the 4-15 days, a third phasecombination of a progestin at a daily dosage selected from the groupconsisting of 40-500 fig trimegestone, 250 μg--4 mg dienogest, and 250μg--4 mg μg drospirenone, and an estrogen at a daily dosage equivalentin estrogenic activity to 10-20 μg ethinyl estradiol, for 4-15 daysbeginning on the day immediately following the last day ofadministration of the second phase combination, wherein the same dosageof the progestin and estrogen combination is administered in each of the4-15 days, and an estrogen phase estrogen at a daily dosage equivalentin estrogenic activity to 5-20 μg ethinyl estradiol, for 3-5 daysbeginning on the day immediately following the last day ofadministration of the third phase combination, wherein the same dosageof the estrogen is administered in each of the 3-5 days, provided thatthe daily dosage of the combination administered in the first phase isnot the same as the daily dosage of the combination administered in thesecond phase and that the daily dosage of the combination administeredin the second phase is not the same as the daily dosage of thecombination administered in the third phase.
 2. The method according toclaim 1, wherein the estrogen estrogen administered in the first,second, and third phase combinations and in the estrogen phase isselected from the group consisting of ethinyl estradiol; 17β-estradiol;conjugated estrogens, USP; estrone or a salt thereof; and mestranol. 3.The method according to claim 2, wherein the estrogen is ethinylestradiol.
 4. The method according to claim 3, whereinthe progestin ofthe first phase combination is administered at a daily dosage selectedfrom the group consisting of 40-75 μg trimegestone, 500-750 μgdienogest, and 500 μg--2 mg drospirenone, the progestin of the secondphase combination is administered at a daily dosage selected from thegroup consisting of 50-125 μg trimegestone, 750 μg--1 mg dienogest, and1-3 mg drospirenone, and the progestin of the third phase combination isadministered at a daily dosage selected from the group consisting of75-250 μg trimegestone, 1-2 mg dienogest, and 2-4 mg drospirenone. 5.The method according to claim 4, wherein the total days ofadministration of the first phase combination plus the second phasecombination plus the third phase combination is
 24. 6. The methodaccording to claim 5, wherein the first phase combination isadministered for 7 days, the second phase combination is administeredfor 7 days, and the third phase combination is administered for 10 days.7. The method according to claim 5, wherein the first phase combinationis administered for 5 days, the second phase combination is administeredfor 5 days, and the third phase combination is administered for 14 days.8. The method according to claim 5, wherein the daily dosage oftrimegestone administered in the first phase combination is 50 μg, thedaily dosage of trimegestone administered in the second phasecombination is 75 μg, the daily dosage of trimegestone administered inthe third phase combination is 125 μg, the daily dosage of ethinylestradiol administered in the first phase combination is 10 μg, thedaily dosage of ethinyl estradiol administered in the second phasecombination is 15 μg, the daily dosage of ethinyl estradiol administeredin the third phase combination is 20 μg, and the daily dosage of ethinylestradiol administered in the estrogen phase is 20 μg.
 9. The methodaccording to claim 5, wherein the daily dosage of dienogest administeredin the first phase combination is 500 μg, the daily dosage of dienogestadministered in the second phase combination is 750 μg, the daily dosageof dienogest administered in the third phase combination is 1 mg, thedaily dosage of ethyl estradiol administered in the first phasecombination is 10 μg, the daily dosage of ethinyl estradiol administeredin the second phase combination is 15 μg, the daily dosage of ethinylestradiol administered in the third phase combination is 20 μg, and thedaily dosage of ethinyl estradiol administered in the estrogen phase is20 μg.
 10. The method according to claim 5, wherein the daily dosage ofdrospirenone administered in the first phase combination is 1 mg, thedaily dosage of drospirenone administered in the second phasecombination is 2 mg, the daily dosage of drospirenone administered inthe third phase combination is 3 mg, the daily dosage of ethinylestradiol administered in the first phase combination is 10 μg, thedaily dosage of ethinyl estradiol administered in the second phasecombination is 15 μg, the daily dosage of ethinyl estradiol administeredin the third phase combination is 20 μg, and the daily dosage of ethinylestradiol administered in the estrogen phase is 20 μg.
 11. The methodaccording to claim 3, whereinthe progestin of the first phasecombination is administered at a daily dosage selected from the groupconsisting of 40-75 μg trimegestone, 500-750 μg dienogest, and 500 μg--2mg drospirenone, the progestin of the second phase combination isadministered at a daily dosage selected from the group consisting of50-125 μg trimegestone, 750 μg--1 mg dienogest, and 1-3 mg drospirenone,and the progestin of the third phase combination is administered at adaily dosage selected from the group consisting of 75-250 μgtrimegestone, 1-2 mg dienogest, and 2-4 mg drospirenone.
 12. The methodaccording to claim 11, wherein the total days of administration of thefirst phase combination plus the second phase combination plus the thirdphase combination is
 24. 13. The method according to claim 12, whereinthe first phase combination is administered for 7 days, the second phasecombination is administered for 10 days, and the third phase combinationis administered for 7 days.
 14. The method according to claim 12,wherein the first phase combination is administered for 6 days, thesecond phase combination is administered for 12 days, and the thirdphase combination is administered for 6 days.
 15. The method accordingto claim 12, wherein the daily dosage of trimegestone administered inthe first phase combination is 50 μg, the daily dosage of trimegestoneadministered in the second phase combination is 125 μg, the daily dosageof trimegestone administered in the third phase combination is 75 μg,the daily dosage of ethinyl estradiol administered in the first phasecombination is 10 μg, the daily dosage of ethinyl estradiol administeredin the second phase combination is 20 μg, the daily dosage of ethinylestradiol administered in the third phase combination is 15 μg, and thedaily dosage of ethinyl estradiol administered in the estrogen phase is15 μg.
 16. The method according to claim 12, wherein the daily dosage ofdienogest administered in the first phase combination is 500 μg, thedaily dosage of dienogest administered in the second phase combinationis 1 mg, the daily dosage of dienogest administered in the third phasecombination is 750 μg, the daily dosage of ethinyl estradioladministered in the first phase combination is 10 μg, the daily dosageof ethinyl estradiol administered in the second phase combination is 20μg, the daily dosage of ethinyl estradiol administered in the thirdphase combination is 15 μg, and the daily dosage of ethinyl estradioladministered in the estrogen phase is 15 μg.
 17. The method according toclaim 12, wherein the daily dosage of drospirenone administered in thefirst phase combination is 500 μg, the daily dosage of drospirenoneadministered in the second phase combination is 2 mg, the daily dosageof drospirenone administered in the third phase combination is 1 mg, thedaily dosage of ethinyl estradiol administered in the first phasecombination is 10 μg, the daily dosage of ethinyl estradiol administeredin the second phase combination is 250 μg, the daily dosage of ethinylestradiol administered in the third phase combination is 250 μg, and thedaily dosage of ethinyl estradiol administered in the estrogen phase is250 μg.
 18. A contraceptive kit adapted for daily oral administrationwhich comprises;3-8 first phase dosage units each containing acombination of a progestin at a daily dosage selected from the groupconsisting of 40-500 μtrimegestone, 250 μg--4 mg dienogest, and 250μg--4 mg drospirenone, and an estrogen at a daily dosage equivalent inestrogenic activity to 10-20 μg ethinyl estradiol, provided that each ofthe dosage units contains the same dosage of progestin and estrogen;4-15 second phase dosage units each containing a combination of aprogestin at a daily dosage selected from the group consisting of 40-500μg trimegestone, 250 μg--4 mg dienogest, and 250 μg--4 mg drospirenone,and an estrogen at a daily dosage equivalent in estrogenic activity to10-20 μg ethinyl estradiol, provided that each of the dosage unitscontains the same dosage of progestin and estrogen, 4-15 third phasedosage units each containing a combination of a progestin at a dailydosage selected from the group consisting of 40-500 μg trimegestone, 250μg--4 mg dienogest, and 250 μg--4 mg drospirenone, and an estrogen at adaily dosage equivalent in estrogenic activity to 10-20 μg ethinylestradiol, provided that each of the dosage units contains the samedosage of progestin and estrogen, and 3-5 estrogen phase dosage unitseach containing an estrogen at a daily dosage equivalent in estrogenicactivity to 5-20 μg ethinyl estradiol, provided that each of the dosageunits contains the same dosage the estrogen, and provided that the dailydosage of the first phase dosage units are not the same as the dailydosage of the second phase dosage units, and that the daily dosage ofthe second phase dosage units are not the same as the daily dosage ofthe third phase dosage units, such that the total number of dosage unitsin the kit equals
 28. 19. The contraceptive kit according to claim 18wherein the estrogen is the same for all three phases and is selectedfrom the group consisting of ethinyl estradiol; 17β-estradiol;conjugated estrogens, USP; estrone or a salt thereof; and mestranol. 20.The contraceptive kit according to claim 19, wherein the total number offirst phase plus second phase plus third phase dosage units equals 24,and the number of estrogen phase dosage units equals 4.